WO2015193217A1 - Dérivés de dihydropyrido[2,3-b]pyrazinone inhibant la protéine bet, à groupe éther ou amino aromatique para-substitué - Google Patents

Dérivés de dihydropyrido[2,3-b]pyrazinone inhibant la protéine bet, à groupe éther ou amino aromatique para-substitué Download PDF

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WO2015193217A1
WO2015193217A1 PCT/EP2015/063276 EP2015063276W WO2015193217A1 WO 2015193217 A1 WO2015193217 A1 WO 2015193217A1 EP 2015063276 W EP2015063276 W EP 2015063276W WO 2015193217 A1 WO2015193217 A1 WO 2015193217A1
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alkyl
phenyl
unsubstituted
dimethyl
monosubstituted
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Norbert Schmees
Bernard Haendler
Detlef STÖCKIGT
Simon Holton
Richard Alexander Bissell
Richard Alexander BOUGLAS
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Bayer Pharma AG
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Bayer Pharma AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to BET protein-inhibiting, in particular BRD4-inhibitory 3,4-dihydropyrido [2,3-b] pyrazinones with> ara-substituted aromatic amino or
  • Ether group pharmaceutical agents containing the compounds of the invention and their prophylactic and therapeutic use in hyper-proliferative diseases, especially in tumor diseases. Furthermore, this invention relates to the use of BET protein inhibitors in viral infections, in neurodegenerative diseases, in inflammatory diseases, in atherosclerotic diseases and in male fertility control.
  • the human BET family (bromodomain and extra C-terminal domain family) has four members (BRD2, BRD3, BRD4 and BRDT) containing two related bromodomains and one extra-terminal domain (Wu and Chiang, J. Biol. Chem., 2007 , 282: 13141-13145).
  • the bromodomains are protein regions that recognize acetylated lysine residues. Such acetylated lysines are often found at the N-terminal end of histones (eg, histone H3 or histone H4) and are features for open chromatin structure and active gene transcription (Kuo and Allis, Bioessays, 1998, 20: 615-626 ).
  • bromodomains can recognize additional acetylated proteins.
  • BRD4 binds to RelA, resulting in the stimulation of NF- ⁇ B and transcriptional activity of inflammatory genes (Huang et al., Mol. Cell. Biol., 2009, 29: 1375-1387).
  • BRD4 also binds to cyclin Tl and forms an active complex important for transcription elongation (Schröder et al., J. Biol. Chem., 2012, 287: 1090-1099).
  • the extra-terminal domain of BRD2, BRD3 and BRD4 interacts with several proteins that have a role in chromatin modulation and regulation of gene expression (Rahman et al., Mol. Cell Biol., 2011, 31: 2641-2652).
  • BET proteins play an important role in cell growth and cell cycle. Biol. Cell, 2009, 20: 4899-4909; Yang et al., Mol. Cell. Biol., 2008, 28: 967-976).
  • a role of BRD4 in the post-mitotic reactivation of gene transcription has been demonstrated (Zhao et al., Nat Cell Biol., 2011, 13: 1295-1304).
  • BRD4 is essential for transcription elongation and recruits the elongation complex P-TEFb, which consists of CDK9 and cyclin Tl, resulting in the activation of RNA polymerase II (Yang et al., Mol. Cell, 2005, 19: 535-545; Schröder et al., J.
  • BRD2 is involved in the regulation of androgen receptor target genes (Draker et al., PLOS Genetics, 2012, 8, el003047). BRD2 and BRD3 bind to transcribed genes in hyperacetylated chromatin regions and promote transcription by RNA polymerase II (LeRoy et al., Mol. Cell, 2008, 30: 51-60).
  • BRD4 Knockdown of BRD4 or inhibition of interaction with acetylated histones in various cell lines results in a Gl residue (Mochizuki et al., J. Biol. Chem., 2008, 283: 9040-9048, Mertz et al. Proc Natl Acad., USA, 2011, 108: 16669-16674). It has also been shown that BRD4 binds to promoter regions of several genes activated in the Gl phase, such as cyclin D1 and D2 (Mochizuki et al., J. Biol. Chem., 2008, 283: 9040-9048 ).
  • BRD2 and BRD4 knockout mice die prematurely during embryogenesis (Gyuris et al., Biochim Biophys Acta, 2009, 1789: 413-421, Houzelstein et al., Mol. Cell Biol., 2002, 22: 3794-3802 ).
  • Heterozygous BRD4 mice have various growth defects attributable to reduced cell proliferation (Houzelstein et al., Mol. Cell. Biol., 2002, 22: 3794-3802).
  • BET proteins play an important role in various tumor types.
  • the fusion between the BET proteins BRD3 or BRD4 and NUT results in an aggressive form of squamous cell carcinoma called NUT midline carcinoma (French, Cancer Genet, Cytogenet., 2010, 203: 16 -20).
  • the fusion protein prevents cell differentiation and promotes proliferation (Yan et al., J. Biol. Chem., 2011, 286: 27663-27675).
  • the growth of derived in vivo models is inhibited by a BRD4 inhibitor (Filippakopoulos et al., Nature, 2010, 468: 1067-1073).
  • BRD4 plays an important role in this tumor (Zuber et al., Nature, 2011, 478, 524-528). Reduction of BRD4 expression leads to selective cell cycle arrest and apoptosis. Treatment with a BRD4 inhibitor prevents the proliferation of an AML xenograft in vivo. Further experiments with a BRD4 inhibitor show that BRD4 plays a role in various hematological tumors, such as multiple myeloma (Delmore et al., Cell, 2011, 146, 904-917) and Burkitt's Lymphoma (Mertz et al. Proc. Natl.
  • BRD4 also plays an important role in solid tumors, such as lung cancer (Lockwood et al., Proc Natl. Acad., USA, 2012, 109, 19408-19413). Increased expression of BRD4 was detected in multiple myeloma, as well as one
  • Amplification of the BRD4 gene has been found in patients with multiple myeloma (Delmore et al., Cell, 2011, 146, 904-917). Amplification of the DNA region containing the BRD4 gene has been detected in primary breast tumors (Kadota et al., Cancer Res, 2009, 69: 7357- 7365). Also for BRD2 there is data related to a role in tumors. A transgenic mouse that selectively overexpressing BRD2 in B cells develops B-cell lymphomas and leukemias (Greenwall et al., Blood, 2005, 103: 1475-1484).
  • BET proteins are also involved in viral infections.
  • BRD4 binds to the E2 protein of various papillomaviruses and is important for survival of the viruses in latently infected cells (Wu et al., Genes Dev., 2006, 20: 2383-2396; Vosa et al., J. Viral., 2006 , 80: 8909-8919).
  • the herpesvirus responsible for Kaposi's sarcoma interacts with various BET proteins, which is important for disease resistance (Viejo-Borbolla et al., J. Viral., 2005, 79: 13618-13629, You et al , J. Viral., 2006, 80: 8909-8919).
  • BRD4 By binding to P-TEFb, BRD4 also plays an important role in the replication of HIV-1 (Bisgrove et al., Proc Natl Acad., USA, 2007, 104: 13690-13695).
  • Treatment with a BRD4 inhibitor stimulates the dormant, untreatable reservoir of HIV-1 virus in T cells (Banerjee et al., J. Leukoc, Biol., 2012, 92, 1147-1154). This reactivation could allow new therapeutic routes to AIDS treatment (Zinchenko et al., J. Leukoc Biol., 2012, 92, 1127-1129).
  • a critical role of BRD4 in DNA replication of polyomaviruses has also been reported (Wang et al., PLoS Pathog., 2012, 8, doi: 10.1371).
  • BET proteins are also involved in inflammatory processes.
  • BRD2-hypomorphic mice show reduced inflammation in adipose tissue (Wang et al., Biochem J., 2009, 425: 71-83).
  • the infiltration of macrophages into white adipose tissue is also reduced in BRD2-deficient mice (Wang et al., Biochem J., 2009, 425: 71-83).
  • BRD4 regulates a number of genes involved in inflammation.
  • Macrophages prevent a BRD4 inhibitor from expression of inflammatory genes, such as IL-1 or IL-6 (Nicodeme et al., Nature, 2010, 468: 1119-1123).
  • BET proteins are also involved in the regulation of the ApoAl gene (Mirguet et al., Bioorg. Med. Chem. Lett., 2012, 22: 2963-2967).
  • the corresponding protein is part of the
  • HDL Higher density lipoprotein
  • BET protein inhibitors may increase the levels of cholesterol HDL and thus potentially be useful for the treatment of atherosclerosis (Mirgu et al., Bioorg. Med. Chem. Lett., 2012, 22: 2963-2967 ).
  • the BET protein BRDT plays an essential role in spermatogenesis through the
  • BRDT is involved in the post-meiotic organization of chromatin (Dhar et al., J. Biol. Chem., 2012, 287: 6387-6405).
  • In vivo experiments in mice show that treatment with a BET inhibitor that also inhibits BRDT results in a decrease in sperm production and infertility (Matzuk et al., Cell, 2012, 150: 673-684). All these studies show that the BET proteins play an essential role in various pathologies and also in male fertility. It would therefore be desirable to find potent and selective inhibitors that prevent the interaction between the BET proteins and acetylated proteins, particularly acetylated histone H4 peptides. These new inhibitors should also have suitable pharmacokinetic properties that allow in vivo, ie in the patient, to inhibit these interactions.
  • 3,4-dihydropyrido [2,3-b] pyrazinones having a> ara-substituted aromatic amino or ether group have the desired properties, i. show a BET protein, in particular a BRD4 protein inhibitory activity.
  • the compounds according to the invention thus represent valuable active ingredients for prophylactic and therapeutic use in hyper-proliferative diseases, in particular in tumor diseases.
  • the compounds according to the invention can be used in viral infections, in neurodegenerative diseases, in inflammatory diseases, in atherosclerotic diseases and in male fertility control come.
  • BRD4 inhibitors were diazepines. So z. B. phenyl-thieno-triazolo-1,4-diazepines (4-phenyl-6-thieno [3,2- [1,2,4] triazolo [4,3-a] [1,4] diazepines) in
  • WO2011 / 143669 (Dana Farber Cancer Institute). Replacement of the thieno by a benzo moiety also results in active inhibitors (J. Med. Chem., 2011, 54, 3827-3838, E. Nicodeme et al., Nature 2010, 468, 1119). Further 4-phenyl-6-thieno [3,2-
  • This application relates to 6-substituted 4i7-isoxazolo [5,4-cf] [2] benzazepines and 4i7-isoxazolo [3,4-cf] [2] benzazepines, including such compounds at position 6 optionally substituted phenyl and also analogues with alternative heterocyclic fusion partners instead of the benzo unit, such as thieno or Pyridoazepine.
  • Another structural class of BRD4 inhibitors is described as 7-isoxazoloquinolines and related quinolone derivatives (Bioorganic & Medicinal Chemistry Letters 22 (2012) 2963-2967).
  • WO2011 / 054845 GaxoSmithKline
  • further benzodiazepines are described as BRD4 inhibitors.
  • BRD4 inhibitors are also described in the following applications: WO2013 / 030150 - 6H-thieno [3,2-f] [l, 2,4] triazolo [4,3-a] [4,3-a ] [l, 4] diazepines,
  • Applicant's application WO 2015/011084 discloses dihydropyridopyazinone derivatives as dual inhibitors of BRD4 and polo-like kinase-1 (PLK-1). In contrast, the compounds according to the invention are substituted 3,4-
  • WO 2013/071217 discloses above all 7,8-dihydropteridin-6 (5H) -one, but also l, 4-dihydropyrido [3,4-b] pyrazine-3 (2H) -one derivatives as inhibitors of kinases, in particular of RSK-1 and RSK-2, as medicaments, inter alia, for the treatment of various
  • the compounds disclosed therein differ from the compounds according to the invention inter alia by the obligate aromatic substitution on the nitrogen atom immediately adjacent to the oxo group (N-5 in the dihydropteridones, or N-4 in the dihydropyrido [3,4-b ] pyrazinones).
  • WO 2010/085570 (Takeda Pharmaceutical Company) describes poly-ADP-ribose polymerase (PARP) inhibitors derived from a variety of bi- and tricyclic scaffolds and 3,4-dihydropyrido [2,3-b] pyrazine -2 (lH) -one derivatives as drugs for the treatment of various diseases.
  • PARP poly-ADP-ribose polymerase
  • the example compounds disclosed therein differ from the compounds according to the invention for example by the type and position of the substitution on the pyrido part of the dihydropyridopyrazinone skeleton.
  • WO 2006/005510 (Boehringer Ingelheim) describes 1,4-dihydropyrido [3,4-b] pyrazine-3 (2H) -one derivatives as inhibitors of PLK-1 for the treatment of hyperproliferative disorders.
  • the position of the pyrido-nitrogen distinguishes the substances disclosed herein from the compounds of the invention.
  • WO 2008/117061 (Sterix Ltd) describes a number of bicyclic chemotypes as inhibitors of steroid sulfatase, inter alia, for use in inhibiting the growth of tumors.
  • US 2006/0019961 (P.E. Mahaney et al.) Describes substituted 3,4-dihydroquinoxaline-2 (1H) -one derivatives as modulators of the estrogen receptor for the treatment of various inflammatory, cardiovascular and autoimmune diseases.
  • WO 2006/050054, WO 2007/134169 and US 2009/0264384 describe a number of bicyclic chemotypes as inhibitors of tumor necrosis factor alpha (TNF- ⁇ ) as well as of various isoforms of phosphodiesterase for the treatment of inter alia inflammatory diseases.
  • WO 2012/088314 discloses a series of bicyclic chemotypes as modulators of pyruvate kinase M2.
  • WO 2003/020722 and WO 2004/076454 (Boehringer Ingelheim) disclose 7,8-dihydropteridine-6 (5H) -ones as inhibitors of specific cell cycle kinases for the treatment of hyperproliferative diseases.
  • WO 2006/018182 (Boehringer Ingelheim) describes pharmaceutical preparations of 7,8-dihydropteridine-6 (5H) -ones in combination, inter alia, with various cytostatic agents for the treatment of tumor diseases.
  • WO 2006/018185 (Boehringer Ingelheim) describes the use of 7,8-dihydropteridine-6 (5H) -ones for the therapy of various tumor diseases.
  • WO 2011/101369 Boehringer Ingelheim
  • WO 2011/113293 Jiangsu Hengrui Medicine
  • WO 2009/141575 Choroma Therapeutics
  • WO 2009/071480 Neviano Medical Sciences
  • WO 2006/021378, WO 2006/021379 and WO 2006 / 021548 disclose further 7,8-dihydropteridine-6 (5H) -one derivatives as inhibitors of PLK-1
  • WO 2007/022638 (Methylgene Inc.) generally discloses HDAC inhibitors of several chemotypes, however, the structures of the exemplified compounds disclosed differ significantly from the compounds of the present invention.
  • WO 1999/050254 (Pfizer) describes a series of bicyclic chemotypes as inhibitors of
  • Serine proteases for antithrombotic therapy differ significantly by the nature and position of the substituents of the inventive compounds.
  • C-6 having an aromatic amino group the phenyl group of which in turn is substituted with a para-position amide group
  • substituted 3,4-dihydroquinoxaline-2 (1H) -one derivatives are indexed by Chemical Abstracts as "Chemical Library” substances without literature reference [see 4 ⁇ [(3R) -4-Cyclopentyl-3-O] ethyl 1-methyl-2-o-1, 2,3,4-tetrahydroquinoxalin-6-yl] amino ⁇ -3-methoxy- / V- [2-methyl-1 - (pyrrolidin-1-yl) propane] 2-yl] benzamide, CAS registry no.
  • A is -NH-, -N (C 1 -C 3 -alkyl) - or -O-,
  • X is -N-, -CH- or -CR 2 -,
  • Y is -N-, -CH- or -CR 2 -,
  • n 0,1 or 2
  • 5-membered monocyclic heteroaryl which is unsubstituted or mono-, di- or trisubstituted by identical or different substituents from halogen, cyano, Ci-C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, halo-Ci-C 4 alkyl, GC 4 -
  • Ci-C t -alkoxycarbonyl with the proviso that the 4- to 8-membered
  • Heterocycloalkyl- is not bound to the rest of the molecule via a nitrogen atom
  • R 2 is hydrogen, hydroxyl, halogen, cyano, C 1 -C 3 -alkyl, C 2 -C 4 -alkenyl, C 2 -C 4 -alkynyl, halogen-C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, Halogeno-C 1 -C 4 -alkoxy, C 1 -C 4 -alkylthio or halogeno-C 1 -C 4 -alkylthio, and if n is 2, R 2 may be identical or different,
  • Ci-Cö-alkyl- which is unsubstituted or monosubstituted with Ci-C3-alkoxy, phenyl, Cs-Cs-cycloalkyl, or 4- to 8-membered
  • phenyl in turn is unsubstituted or mono-, di- or trisubstituted by identical or different substituents with halogen, cyano, C 1 -C 4 -alkyl-, C 2 -C -alkenyl-, C 2 -C -alkynyl-, Ci C 1-4 alkoxy, halo C 1 -C 4 alkyl or halo C 1 -C 4 alkoxy, and
  • Cs-Cs-cycloalkyl and 4- to 8-membered heterocycloalkyl are in turn unsubstituted or substituted once or twice, identically or differently, by C 1 -C 3 -alkyl-,
  • Ci-Cö-alkyl- which is unsubstituted or monosubstituted with cyano, Ci-C3-alkoxy, Ci-C3-alkylamino, phenyl, Cs-Cs-cycloalkyl, or 4- to 8-membered heterocycloalkyl,
  • phenyl in turn is unsubstituted or mono-, di- or trisubstituted by identical or different substituents from Ci-C with halo, cyano, 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl C 1 -C 4 -alkoxy, C 1 -C 4 -alkyl or C 1 -C 4 -alkoxy-, and
  • Cs-Cs-cycloalkyl and 4- to 8-membered heterocycloalkyl are in turn unsubstituted or substituted once or twice, identically or differently, by C 1 -C 3 -alkyl-,
  • heterocycloalkyl 8-membered heterocycloalkyl, heterospirocycloalkyl, heterobicycloalkyl or bridged heterocycloalkyl, which are unsubstituted or mono- or are substituted twice, identically or differently with hydroxyl, fluorine, oxo, cyano, C 1 -C 3 -alkyl, fluorine-C 1 -C 3 -alkyl, C 3 -C 6 -cycloalkyl, cyclopropylmethyl-C 1 -C 5 -alkylcarbonyl, C3-alkylamino (Ci-C3 alkyl) - or
  • A is -NH- or -N (methyl) -
  • X is -N- or -CH-
  • Y stands for -CH-
  • n 0,1 or 2
  • 5- to 6-membered heterocycloalkyl- which is unsubstituted or monosubstituted with Ci-C3-alkyl- or Ci-C t-alkoxycarbonyl-, with the proviso that the 5- to 6-membered heterocycloalkyl- not over a nitrogen atom is attached to the rest of the molecule,
  • R 2 is hydrogen, hydroxy, fluorine, chlorine, cyano, methyl, trifluoromethyl,
  • R 2 may be the same or different,
  • R 3 represents methyl or ethyl
  • R 4 is hydrogen, methyl or ethyl
  • R 5 is hydrogen, methyl or ethyl
  • R 6 is C 2 -C 5 alkyl group
  • phenyl is in turn unsubstituted or mono-, di- or trisubstituted by identical or different substituents with fluorine, chlorine, bromine, cyano, C 1 -C 3 -alkyl or C 1 -C 3 -alkoxy-, and
  • phenyl- or 5- to 6-membered heteroaryl- which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, chlorine, methyl or 6-membered heterocycloalkyl-,
  • 6-membered heterocycloalkyl is in turn unsubstituted or monosubstituted by methyl or ieri-butoxycarbonyl
  • C 1 -C 6 -alkyl which is unsubstituted or monosubstituted by cyano, C 1 -C 3 -alkoxy, C 1 -C 3 -alkylamino, phenyl or 4 to 8-membered
  • phenyl- in turn is unsubstituted or mono-, di- or trisubstituted by identical or different substituents with fluorine, chlorine, bromine, cyano, Ci-Cs-alkyl or Ci-C 3 alkoxy, and
  • Cs-Cs-cycloalkyl or 4- to 8-membered heterocycloalkyl- which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with Ci-C 3 alkyl or Ci-C t -alkoxycarbonyl, with with the proviso that the 4- to 8-membered heterocycloalkyl is not bound via a nitrogen atom to the carbonyl, sulfinyl or sulfonyl group in R 1 , and
  • 5- to 6-membered heterocycloalkyl is in turn unsubstituted or monosubstituted or disubstituted by identical or different substituents with C1-C3-alkyl-,
  • Heterocycloalkyl- which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with hydroxyl, fluorine, oxo, Ci-C3-alkyl, fluoro-Ci-C3-alkyl, cyclopropyl, cyclopropylmethyl, acetyl, teri-butoxycarbonyl or (H 3 C) 2 N- (C 1 -C 3 -alkyl) -, and their diastereomers, racemates, polymorphs and physiologically acceptable salts.
  • A stands for -NH-
  • X is -N- or -CH-
  • Y stands for -CH-
  • n 0 or 1
  • R 2 is Is hydrogen, fluorine, chlorine, methyl, trifluoromethyl or methoxy
  • R 3 is methyl
  • R 4 is methyl or ethyl
  • R 5 represents hydrogen
  • R 6 is C 3 -C 5 -alkyl-
  • methyl which is monosubstituted with phenyl- or 4- to 6-membered heterocycloalkyl-, wherein the 4- to 6-membered heterocycloalkyl is in turn unsubstituted or monosubstituted with methyl,
  • phenyl which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, chlorine or methyl,
  • Ci-C t-alkyl- which is unsubstituted or monosubstituted with cyano
  • phenyl is in turn unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, chlorine, cyano, methyl or methoxy, and
  • Heterocycloalkyl- is not bound via a nitrogen atom to the carbonyl, sulfinyl or sulfonyl group in R 1 , and
  • Heterocycloalkyl- which are unsubstituted or monosubstituted with Ci-C 3 alkyl, trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, acetyl, ieri-butoxycarbonyl or 2- (N, N- Dimethylamino) ethyl, their diastereomers, racemates, polymorphs and physiologically acceptable salts.
  • piperidinyl which is unsubstituted or monosubstituted with methyl, with the proviso that the piperidinyl is not bound to the rest of the molecule via a nitrogen atom,
  • piperidinyl which is unsubstituted or monosubstituted with methyl, with the proviso that the piperidinyl is not bound via a nitrogen atom via a nitrogen atom to the carbonyl, sulfinyl or sulfonyl group in R 1 , and
  • A stands for -NH-
  • X is -N- or -CH-
  • Y stands for -CH-
  • n 0 or 1
  • R 1 for bromine, cyano or for
  • R 2 is hydrogen, fluorine, methyl, trifluoromethyl or methoxy
  • R 3 is methyl
  • R 4 is methyl, stands for hydrogen
  • A is -NH-, -N (C 1 -C 3 -alkyl) - or -O-,
  • X is -N-, -CH- or -CR 2 -,
  • Y is -N-, -CH- or -CR 2 -,
  • n 0,1 or 2
  • R U is hydrogen, hydroxy, halogen, cyano, C 1 -C 3 -alkyl, C 2 -C 4 -alkenyl, C 2 -C 4 -alkynyl, halogeno-C 1 -C 4 - alkyl, C 1 -C 4 -alkoxy, halogeno-C 1 -C 4 -alkoxy, C 1 -C 4 -
  • R 4 is hydrogen or C 1 -C 3 -alkyl-
  • R 5 is hydrogen or C 1 -C 3 -alkyl
  • Ci-Cö-alkyl- which is unsubstituted or monosubstituted with C1-C3-alkoxy, phenyl, Cs-Cs-cycloalkyl, or 4- to 8-membered heterocycloalkyl, in which phenyl is in turn unsubstituted or mono-, di- or trisubstituted by identical or different substituents with halogen, cyano, GC 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkoxy , Halogeno-C 1 -C 4 -alkyl or halogeno-C 1 -C 4 -alkoxy-, and
  • Cs-Cs-cycloalkyl and 4- to 8-membered heterocycloalkyl are in turn unsubstituted or substituted once or twice, identically or differently, by C 1 -C 3 -alkyl-,
  • phenyl or 5- to 6-membered heteroaryl which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with halogen, C1-C3-alkyl or 4- to 8-membered heterocycloalkyl-,
  • C 1 -C 6 -alkyl which is unsubstituted or monosubstituted by cyano, C 1 -C 3 -alkoxy, C 1 -C 3 -alkylamino, phenyl, C 3 -C 8 -cycloalkyl, or 4 to 8 - heterozygous heterocycloalkyl,
  • phenyl in turn is unsubstituted or mono-, di- or trisubstituted by identical or different substituents from Ci-C with halo, cyano, 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl , GC 4 alkoxy, haloCG 4 alkyl or halo-Ci-C 4 alkoxy, and
  • Cs-Cs-cycloalkyl and 4- to 8-membered heterocycloalkyl are in turn unsubstituted or monosubstituted or disubstituted by identical or different substituents with G-Cs-alkyl-,
  • Cs-Cs-cycloalkyl or 4- to 8-membered heterocycloalkyl which are unsubstituted or mono- or disubstituted by identical or different substituents selected from Ci-C 3 alkyl or Ci-C 4 alkoxycarbonyl, with the proviso that the 4- to 8-membered heterocycloalkyl is not bound via a nitrogen atom to the carbonyl or sulfonyl group in R 1 ,
  • R 9 is C 1 -C 6 -alkyl or C 3 -C 8 -cycloalkyl-,
  • R 10 and R 11 independently of one another are hydrogen or unsubstituted or mono- or disubstituted by identical or different hydroxy, oxo or Ci-C 3 alkoxy-substituted Ci-C3-alkyl, or fluoro-C 1 -C 3 -alkyl or 4- to 8-membered heterocycloalkyl-,
  • R 12 is C 1 -C 6 -alkyl or phenyl-C 1 -C 3 -alkyl-,
  • A is -NH- or -N (methyl) -
  • X is -N- or -CH-
  • Y stands for -CH-
  • n 0,1 or 2
  • oxazolyl, thiazolyl, oxadiazolyl or thiadiazolyl which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with halogen, cyano, C 1 -C 3 -alkyl-, trifluoromethyl-, C 1 -C 3 -alkoxy-, Trifluoromethoxy or -NR 10 R U ,
  • R 2 is hydrogen, hydroxy, fluorine, chlorine, cyano, methyl, methoxy, ethyl or
  • R 2 may be the same or different
  • R 3 represents methyl or ethyl
  • R 4 is hydrogen, methyl or ethyl, represents hydrogen, methyl or ethyl,
  • phenyl is in turn unsubstituted or mono-, di- or trisubstituted by identical or different substituents with fluorine, chlorine, bromine, cyano, Ci-C3-alkyl or Ci-C3-alkoxy, and
  • phenyl- or 5- to 6-membered heteroaryl- which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, chlorine, methyl or 6-membered heterocycloalkyl-,
  • 6-membered heterocycloalkyl is in turn unsubstituted or monosubstituted by methyl or ieri-butoxycarbonyl
  • Ci-Cö-alkyl- which is unsubstituted or monosubstituted with cyano, Ci-C3-alkoxy, Ci-C3-alkylamino, phenyl or 4- to 8-membered
  • phenyl is in turn unsubstituted or mono-, di- or trisubstituted by identical or different substituents with fluorine, chlorine, bromine, cyano, Ci-C3-alkyl or Ci-C3-alkoxy, and
  • Cs-Cs-cycloalkyl or 4- to 8-membered heterocycloalkyl- which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with Ci-C3-alkyl- or Ci-C t-alkoxycarbonyl, with the
  • the 4- to 8-membered heterocycloalkyl group is not bonded via a nitrogen atom to the carbonyl or sulfonyl group in R 1 , and independently of one another are hydrogen or unsubstituted or monosubstituted or C 1 -C 3 -alkyl or hydroxy or oxo-substituted heterocycloalkyl-,
  • heterocycloalkyl- which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with hydroxyl, fluorine, oxo, C 1 -C 3 -alkyl-, fluoro-C 1 -C 3 -alkyl-, cyclopropyl-, cyclopropylmethyl- , Acetyl or tert-butoxycarbonyl, and their diastereomers, racemates, polymorphs and physiologically acceptable salts.
  • A stands for -NH-
  • X is -N- or -CH-
  • Y stands for -CH-
  • n 0 or 1
  • R 2 is hydrogen, fluorine, chlorine, methyl or methoxy
  • R 3 is methyl
  • R 4 is methyl or ethyl
  • R 5 represents hydrogen
  • R 6 is C 3 -C 5 -alkyl-
  • phenyl which is unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, chlorine or methyl,
  • R 7 is C 1 -C 4 -alkyl which is unsubstituted or monosubstituted with cyano
  • phenyl in which phenyl is in turn unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, chlorine, cyano, methyl or
  • R 10 and R 11 independently of one another represent hydrogen or C 1 -C 3 -alkyl
  • R 10 and R 11 together with the nitrogen atom to which they are attached, for 5- to
  • 6-membered heterocycloalkyl which is unsubstituted or monosubstituted by C 1 -C 3 -alkyl-, trifluoromethyl-, difluoromethyl-, 2,2,2-
  • Trifluoroethyl or ieri-butoxycarbonyl and their diastereomers, racemates, polymorphs and physiologically acceptable salts.
  • A stands for -NH-
  • X is -N- or -CH-
  • Y stands for -CH-
  • n 0 or 1
  • R 2 is hydrogen, methyl or methoxy
  • R 3 is methyl
  • R 4 is methyl
  • R 5 represents hydrogen
  • R 6 is isopropyl
  • R 7 is C 1 -C 3 -alkyl which is unsubstituted or monosubstituted with cyano, or
  • Heterocycloalkyl- stand which is unsubstituted or monosubstituted with
  • A stands for -NH-
  • X is -N- or -CH-
  • Y stands for -CH-
  • n 0 or 1
  • R 1 for bromine, cyano or for
  • Preference is given to compounds of the general formula (I) in which n is the number 0.
  • Preference is given to compounds of the general formula (I) in which n is the number 1.
  • 5- to 6-membered heterocycloalkyl- which is unsubstituted or monosubstituted with Ci-C 3 alkyl- or Ci-C t-alkoxycarbonyl-, with the proviso that the 5- to 6-membered
  • Heterocycloalkyl does not have a nitrogen atom attached to the rest of the molecule.
  • oxazolyl, thiazolyl, oxadiazolyl or thiadiazolyl which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with halogen, cyano, C 1 -C 3 -alkyl, trifluoromethyl, C 1 -C 3 -alkoxy , Trifluoromefhoxy- or -NR 10 R U.
  • R 1 is isoxazolyl, oxazolyl, thiazolyl, oxadiazolyl or thiadiazolyl, which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with halogen, cyano, C 1 -C 3 -alkyl, trifluoromethyl, C 1 -C 3 -alkoxy, trifluoromethoxy or -NR 10 R U.
  • R 1 is oxazolyl, thiazolyl, oxadiazolyl or thiadiazolyl, which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with halogen, cyano, C 1 -C 3 Alkyl, trifluoromethyl, Ci-C3-alkoxy, trifluoromethoxy or -NR 10 R U.
  • R 1 is 5- to 6-membered heterocycloalkyl- which is unsubstituted or monosubstituted by C 1 -C 3 -alkyl- or C 1 -C 4 -alkoxycarbonyl-, with which Provided that the 5- to 6-membered heterocycloalkyl- is not bound via a nitrogen atom to the rest of the molecule.
  • piperidinyl or pyrrolidinyl which are unsubstituted or monosubstituted with Ci-C3-alkyl, with the proviso that the piperidinyl and the pyrrolidinyl- is not bound via a nitrogen atom to the rest of the molecule.
  • R 1 is isoxazolyl, oxazolyl or oxadiazolyl, which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with C 1 -C 3 -alkyl-.
  • R 1 is oxazolyl or oxadiazolyl which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with C 1 -C 3 -alkyl-.
  • R 1 is piperidinyl or pyrrolidinyl, which are unsubstituted or monosubstituted with C 1 -C 3 -alkyl, with the proviso that the piperidinyl and the pyrrolidinyl is not bound by a nitrogen atom to the rest of the molecule.
  • Halogen, cyano, or -NR 10 R U or is oxazolyl which is unsubstituted or monosubstituted or disubstituted with methyl.
  • R 1 is isoxazolyl, which is unsubstituted or monosubstituted or disubstituted by methyl.
  • Piperidinyl is unsubstituted or monosubstituted with methyl, provided that the piperidinyl is not attached to the rest of the molecule via a nitrogen atom.
  • R 2 is hydrogen, fluorine, methyl or methoxy.
  • Trifluoromethyl stands. Particular preference is given to compounds of the general formula (I) in which R 2 is fluorine.
  • R 6 is C 2 -C 8 -alkyl-, is methyl or ethyl which is monosubstituted by C 1 -C 3 -alkoxy, phenyl or 4 to 8-membered heterocycloalkyl-,
  • phenyl or 5- to 6-membered heteroaryl- which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, chlorine, methyl or 6-membered heterocycloalkyl-,
  • 6-membered heterocycloalkyl is in turn unsubstituted or monosubstituted with methyl or ieri-butoxycarbonyl.
  • 5- to 6-membered heteroaryl- which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, chlorine, methyl or 6-membered heterocycloalkyl, in which the 6-membered heterocycloalkyl is in turn unsubstituted or simply is substituted with methyl or ieri-butoxycarbonyl.
  • phenyl is in turn unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, chlorine, cyano, methyl or methoxy, and
  • R 6 is C 3 -C 5 -alkyl-.
  • phenyl is in turn unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, chlorine, cyano, methyl or methoxy, and
  • Tetrahydropyran-4-yl or / V-methyl-piperidin-4-yl Tetrahydropyran-4-yl or / V-methyl-piperidin-4-yl.
  • R 7 is C 1 -C 6 -alkyl- which is unsubstituted or monosubstituted by cyano, C 1 -C 3 -alkoxy-, C 1 -C 3 -alkylamino-, phenyl or 4- to 8-membered heterocycloalkyl-, wherein phenyl- in turn unsubstituted or mono-, di- or trisubstituted by identical or different substituents with fluorine, chlorine, bromine, cyano, Ci-C 3 alkyl or
  • Ci-C t-alkoxycarbonyl with the proviso that the 4- to 8-membered heterocycloalkyl is not bound via a nitrogen atom to the carbonyl, sulfinyl or sulfonyl group in R 1 .
  • R 7 is C 1 -C 6 -alkyl-, which is unsubstituted or monosubstituted by cyano, C 1 -C 3 -alkoxy, C 1 -C 3 -alkylamino, phenyl or cyano 4- to 8-membered heterocycloalkyl,
  • Ci-C t-alkoxycarbonyl with the proviso that the 4- to 8-membered heterocycloalkyl is not bound via a nitrogen atom to the carbonyl or sulfonyl group in R 1 .
  • R 7 is C 1 -C 6 -alkyl- which is unsubstituted or monosubstituted by cyano, C 1 -C 3 -alkoxy-, C 1 -C 3 -alkylamino-, phenyl or 4- to 8-membered heterocycloalkyl-,
  • R 7 is Cs-Cs-cycloalkyl or 4- to 8-membered heterocycloalkyl- which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with Ci-C3
  • the 4- to 8-membered heterocycloalkyl is not attached via a nitrogen atom to the carbonyl, sulfinyl or sulfonyl group in R 1 .
  • R 7 is Cs-Cs-cycloalkyl or 4- to 8-membered heterocycloalkyl- which are unsubstituted or monosubstituted or disubstituted by identical or different substituents with Ci-C3
  • the 4- to 8-membered heterocycloalkyl- is not bound via a nitrogen atom to the carbonyl or sulfonyl group in R 1 -alkyl or Ci-C t -alkoxycarbonyl.
  • R 7 is C 1 -C 4 -alkyl- which is unsubstituted or monosubstituted by cyano, phenyl or 5- to 6-membered heterocycloalkyl-,
  • phenyl is in turn unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, chlorine, cyano, methyl or methoxy, and
  • R 7 is C 1 -C 4 -alkyl- which is unsubstituted or monosubstituted by cyano, phenyl or 5- to 6-membered heterocycloalkyl-,
  • phenyl is in turn unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, chlorine, cyano, methyl or methoxy, and
  • R 7 is C 1 -C 4 -alkyl- which is unsubstituted or monosubstituted by cyano, phenyl or 5- to 6-membered heterocycloalkyl-,
  • phenyl is in turn unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, chlorine, cyano, methyl or methoxy, and
  • R 7 is C 1 -C 4 -alkyl, which is unsubstituted or monosubstituted with cyano.
  • R 7 is C 1 -C 4 -alkyl- which is unsubstituted or monosubstituted by phenyl-,
  • phenyl in which phenyl is in turn unsubstituted or monosubstituted or disubstituted by identical or different substituents with fluorine, chlorine, cyano, methyl or methoxy.
  • R 7 is C 1 -C 4 -alkyl- which is unsubstituted or monosubstituted by 5- to 6-membered heterocycloalkyl-, in which the 5- to 6-membered group Heterocycloalkyl- in turn is unsubstituted or monosubstituted with Ci-C3-alkyl-.
  • 5- to 6-membered heterocycloalkyl which is unsubstituted or monosubstituted with Ci-C3-alkyl, with the proviso that the 5- to 6-membered heterocycloalkyl- not via a nitrogen atom to the carbonyl, sulfinyl or sulfonyl group is bound in R 1 .
  • Ci-C3-alkyl- which is unsubstituted or monosubstituted with cyano
  • piperidinyl which is unsubstituted or monosubstituted with methyl, with the proviso that the piperidinyl is not bound via a nitrogen atom to the carbonyl, sulfinyl or sulfonyl group in R 1 .
  • Ci-C 3 -alkyl- which is unsubstituted or monosubstituted with cyano
  • R 7 is piperidinyl which is unsubstituted or monosubstituted with methyl, with the proviso that the piperidinyl does not have a nitrogen atom on the carbonyl, Sulfinyl or sulfonyl group is bound in R 1 .
  • R 10 and R 11 independently of one another are hydrogen or unsubstituted or monosubstituted or C 1 -C 3 -alkyl or hydroxy or oxo-substituted heterocycloalkyl-,
  • heterospirocycloalkyl or bridged heterocycloalkyl are unsubstituted or monosubstituted or disubstituted by identical or different substituents Hydroxyl, fluorine, oxo, C 1 -C 3 -alkyl, fluoro-C 1 -C 3 -alkyl, cyclopropyl, cyclopropylmethyl, acetyl, ieri-butoxycarbonyl or (H 3 C) 2 N - (C 1 -C 3 -alkyl ) -.
  • R 10 and R 11 independently of one another are hydrogen or unsubstituted or monosubstituted or C 1 -C 3 -alkyl or hydroxy or oxo-substituted heterocycloalkyl-,
  • R and R independently of one another are hydrogen or C 1 -C 3 -alkyl which is unsubstituted or monosubstituted by hydroxyl or oxo or is 5 to 6-membered heterocycloalkyl-,
  • 5- to 6-membered heterocycloalkyl is in turn unsubstituted or mono- or disubstituted by identical or different substituents with Ci-C 3 alkyl.
  • Heterospirocycloalkyl- or bridged Heterocycloalkyl- standing which are unsubstituted or mono- or disubstituted by identical or different substituents with hydroxyl, fluorine, oxo, Ci-C 3 alkyl, fluoro-Ci-C 3 alkyl, cyclopropyl, Cyclopropylmethyl, acetyl, ieri-butoxycarbonyl or (H 3 C) 2 N- (C 1 -C 3 -alkyl) -.
  • R 10 and R 11 independently of one another, are hydrogen or C 1 -C 3 -alkyl or acetyl
  • R 10 and R 11 together with the nitrogen atom to which they are attached, for 5- to
  • R 10 and R 11 together with the nitrogen atom to which they are attached, for 5- to
  • 6-membered Heterocycloalkyl- which is unsubstituted or monosubstituted with Ci-C3-alkyl, trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl or ieri-butoxycarbonyl-.
  • R 10 and R 11 independently of one another, are hydrogen or C 1 -C 3 -alkyl or acetyl.
  • R 10 and R 11 independently of one another, are hydrogen or C 1 -C 3 -alkyl-.
  • Heterocycloalkyl Heterospirocycloalkyl- or bridged Heterocycloalkyl- stand, which are unsubstituted or monosubstituted with Ci-C3-alkyl, trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, acetyl, ieri-butoxycarbonyl or 2 - (N, N-dimethylamino) ethyl.
  • Heterocycloalkyl- which is unsubstituted or monosubstituted with Ci-C 3 alkyl, trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl or ieri-butoxycarbonyl-.
  • R 10 and R 11 independently of one another, are C 1 -C 3 -alkyl or acetyl
  • Heterocycloalkyl- stand which is unsubstituted or monosubstituted with
  • Heterocycloalkyl- stand which is unsubstituted or monosubstituted with
  • R 3 is methyl
  • R 4 is methyl
  • R 5 is hydrogen
  • Ci-Cö-alkyl or a Ci-Cö-alkyl group is meant a linear or branched, saturated, monovalent hydrocarbon radical, such. a methyl, ethyl, propyl, butyl, pentyl, hexyl, where-propyl, where-butyl, sec-butyl, tert-butyl, where-pentyl, 2-methylbutyl, 1- Methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, eo-pentyl, 1,1-dimethylpropyl,
  • Ci-Cö-alkyl or a Ci-Cö-alkyl group Ci-C4-alkyl, C2-C4-alkyl or C 2 -Cs-alkyl, more preferably Ci-C3-alkyl or a methyl, ethyl , Propyl or isopropyl radical to understand.
  • C 2 -C -alkylene, or a C 2 -C -alkylene group is to be understood as meaning a linear or branched, saturated, divalent hydrocarbon radical, such as, for example, an ethylene, propylene, butylene, pentylene, or propylene -, where-butylene, sec-butylene, ieri-butylene, where-pentylene, 2-methylbutylene, 1-methylbutylene, 1-ethylpropylene, 1,2-dimethylpropylene, eo-pentylene or
  • C2-C4-alkenyl or a C2-C4-alkenyl group is meant a linear or branched, monovalent hydrocarbon radical having one or two C double bonds, such as an ethenyl, (£) -prop-2 -enyl, (Z) -prop-2-enyl, allyl (prop-l-enyl), allenyl-buten-1-yl, or buta-l, 3-dienyl radical.
  • C 2 -C 4 -alkynyl or a C 2 -C 4 -alkynyl group
  • a C 1 -C 4 -alkoxy or C 1 -C 4 -alkoxy group is to be understood as meaning a linear or branched, saturated alkyl ether radical -O-alkyl, for example a methoxy, ethoxy, n-propoxy, isopropoxy or ieri.-butoxy radical.
  • C 1 -C 4 -alkoxy or C 1 -C 4 -alkoxy is preferably understood to mean C 1 -C 3 -alkoxy, particularly preferably a methoxy or ethoxy radical.
  • C 1 -C 4 -alkylthio or a C 1 -C 4 -alkylthio group is to be understood as meaning a linear or branched, saturated alkylthioether radical -S-alkyl, for example a methylthio, ethylthio, n-propylthio, isopropylthio, or ferric butyl residual.
  • C 1 -C 4 -alkylthio or a C 1 -C 4 -alkylthio group is understood to mean C 1 -C 3 -alkylthio, particularly preferably a methylthio or ethylthio radical.
  • a C 1 -C 3 -alkylamino or a C 1 -C 3 -alkylamino group is understood to mean an amino radical having one or two (independently selected) alkyl substituents having 1 to 3 carbon atoms as defined above.
  • (C 1 -C 3 ) -alkylamino is, for example, a monoalkylamino radical having 1 to 3 carbon atoms or a dialkylamino radical having 1 to 3 carbon atoms per molecule
  • Examples include:
  • the heteroatom -NH- can optionally be substituted by C 1 -C 3 -alkyl,
  • Oxo may be attached to atoms of suitable valency, for example to a saturated carbon atom or to sulfur.
  • the bond to carbon is to form a carbonyl group.
  • halogen is meant fluorine, chlorine, bromine or iodine.
  • Fluorine, chlorine, bromine or iodine which is optionally substituted on the phenyl ring can be in the ortho, meta or ortho position. Preference is given to fluorine or chlorine.
  • the preferred position is the meta and / or ara position.
  • a halogeno-C 1 -C 4 -alkyl radical is a C 1 -C 4 -alkyl radical having at least one
  • Halogen substituents preferably having at least one fluorine substituent to understand.
  • fluoro-C 1 -C 3 -alkyl radicals for example difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl or pentafluoroethyl.
  • phenyl-C 1 -C 3 -alkyl is meant a group which is composed of an optionally substituted phenyl radical and a C 1 -C 3 -alkyl group and which are bonded via the C 1 -C 3 -alkyl group to the rest of the molecule is.
  • Benzyl is preferred.
  • a halo-C 1 -C 4 -alkoxy radical is a C 1 -C 4 -alkoxy radical having at least one
  • Halogen substituents preferably having at least one fluorine substituent to understand.
  • fluoro-C 1 -C 3 -alkoxy radicals for example difluoromethoxy, trifluoromethoxy and 2,2,2-trifluoroethoxy radicals.
  • a halogeno-C 1 -C 4 -alkylthio radical is to be understood as meaning a C 1 -C 4 -alkylthio radical having at least one halogen substituent, preferably having at least one fluorine substituent.
  • fluorine-C 1 -C 3 -alkylthio radicals in particular trifluoromethylthio radicals.
  • a C 1 -C 3 -alkylcarbonyl radical is to be understood as meaning a C 1 -C 3 -alkyl-C (0O) group. Preference is given to acetyl- or propanoyl-.
  • a C 1 -C 4 -alkoxycarbonyl radical is to be understood as meaning a C 1 -C 4 -alkoxy-C (0O) group.
  • Preferred is methoxycarbonyl, ethoxycarbonyl, and ferric. Butoxycarbonyl.
  • a C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl radical is to be understood as meaning a C 1 -C 4 -alkyl radical substituted by C 1 -C 4 -alkoxy, such as, for example, B.Methoxymethyl, methoxyethyl, ethoxymethyl or ethoxyethyl.
  • aryl an unsaturated fully conjugated system made up of carbon atoms which has 3, 5 or 7 conjugated double bonds, e.g. Phenyl, naphthyl or phenanthryl. Preference is given to phenyl.
  • Heteroaryl is to be understood as meaning ring systems which have an aromatic-conjugated ring system and contain at least one and up to five heteroatoms as defined above.
  • ring systems may have 5, 6 or 7 ring atoms or, in the case of condensed or benzo-fused ring systems, also combinations of 5- and 6-membered ring systems, 5- and 5-membered ring systems or also 6- and 6-membered ring systems , Examples include ring systems such as pyrrolyl, pyrazolyl,
  • Imidazolyl triazolyl, tetrazolyl, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, oxazinyl, indolyl, benzimidazolyl, Indazolyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, benzofuryl, benzothienyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, imidazopyridinyl or benzoxazinyl.
  • 5- to 6-membered monocyclic heteroaryl for example pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl.
  • 5-membered monocyclic heteroaryl for example, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl.
  • C3-C6-cycloalkyl C3-Cs-cycloalkyl, or Cs-Cs-cycloalkyl is meant a monocyclic, built exclusively from carbon atoms, saturated ring system having 3 to 6, 3 to 8 atoms, or 5 to 8 atoms. Examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • C t -C 6 -cycloalkenyl, C t -Cs -cycloalkenyl, or Cs-Cs-cycloalkenyl is a monocychal, monocyclic or polyunsaturated, non-aromatic ring system with 4 to 6, 4 to 8 atoms, or exclusively composed of carbon atoms, respectively To understand 5 to 8 atoms.
  • Examples are cyclobuten-1-yl, cyclopenten-1-yl, cyclohexene-2-yl, cyclohexene-1-yl and cycloocta-2,5-dienyl.
  • Heterocycloalkyl is to be understood as meaning a 4- to 8-membered monocyclic, saturated ring system which has 1 to 3 heteroatoms as defined above, in any desired combination. Preference is given to 4- to 7-membered heterocycloalkyl groups, particularly preferred are 5- to 6-membered heterocycloalkyl groups.
  • Heterospirocycloalkyl- is a bicyclic, saturated ring system with a total of 6 to 11 ring atoms to understand in which the two rings share a common atom, and which has 1 to 3 heteroatoms as defined above, in any combination.
  • Examples are azaspiro [2.3] hexyl, azaspiro [3.3] heptyl, oxaazaspiro [3.3] heptyl,
  • Heterobicycloalkyl- is a bicyclic, saturated ring system with altogether 6 to 10
  • ring atoms in which the two rings share two directly adjacent atoms, and which has 1 to 3 heteroatoms as defined above, in any combination.
  • Examples are azabicyclo [3.3.0] octyl, azabicyclo [4.3.0] nonyl,
  • bridged heterocycloalkyl- is meant a bicyclic, saturated ring system having a total of 6 to 10 ring atoms, in which the two rings share two two atoms which are not directly adjacent to each other, and which has 1 to 3 heteroatoms as defined above, in any combination.
  • Examples are azabicyclo [2.2.1] heptyl,
  • Heterocycloalkenyl is a 4- to 8-membered monocyclic, mono- or polyunsaturated, non-aromatic ring system which has 1 to 3 heteroatoms as defined above, in any desired combination. Preference is given to 4- to 7-membered heterocycloalkyl groups, particularly preferred are 5- to 6-membered heterocycloalkyl groups.
  • Examples which may be mentioned are 4H-pyranyl, 2H-pyranyl, 2,5-dihydro-1H-pyrrolyl, [1,3] dioxolyl, 4H- [1,3,4] thiadiazinyl, 2,5-dihydrofuranyl, 2,3- Dihydrofuranyl, 2,5-dihydrothiophenyl, 2,3-dihydrothiophenyl, 4,5-dihydrooxazolyl, and 4H- [1,4] thiazinyl.
  • Compounds of the invention are the compounds of the general formula (I) and their salts, solvates and solvates of the salts, the compounds of the formulas below and their salts, solvates and solvates of the salts of the general formula (I) and of the general formula (I) included, hereinafter referred to as exemplary embodiments
  • Salts used in the context of the present invention are physiologically acceptable salts of the compounds according to the invention. However, also included are salts which are not suitable for pharmaceutical applications themselves but can be used, for example, for the isolation or purification of the compounds according to the invention.
  • Physiologically acceptable salts of the compounds of the invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, e.g. Salts of
  • Solvates in the context of the invention are those forms of the compounds according to the invention which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a special form of solvates that coordinate with water. As solvates, hydrates are preferred in the context of the present invention.
  • the compounds of the invention may exist in different stereoisomeric forms depending on their structure, i. in the form of configurational isomers or optionally also as conformational isomers.
  • the compounds of the invention can am
  • Asymmetric center may therefore be present as pure enantiomers, racemates but also as diastereomers or mixtures thereof, if one or more of the substituents described in the formula (I) contains a further asymmetric element, for example a chiral carbon atom.
  • the present invention therefore also encompasses diastereomers and their respective mixtures. From such mixtures, the pure stereoisomers in known Isolate way; Preferably, for this purpose, chromatographic methods are used, in particular HPLC chromatography on chiral or achiral phase.
  • the enantiomers according to the invention inhibit the different degrees of inhibition
  • Another object of the present invention are enantiomeric mixtures of the (3R) - configured compounds of the invention with their (3S) enantiomers, in particular the corresponding racemates and mixtures of enantiomers in which outweighs the (3R) form.
  • the present invention encompasses all tautomeric forms.
  • the present invention also includes all suitable isotopic variants of the compounds of the invention.
  • An isotopic variant of a compound according to the invention is understood to mean a compound in which at least one atom within the
  • Compound according to the invention is exchanged for another atom of the same atomic number, but with a different atomic mass than the atomic mass usually or predominantly occurring in nature.
  • isotopes which can be incorporated into a compound of the invention are those of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as 2 H (deuterium), 3 H (tritium), U C, 13 C, 14 C, 15 N, 17 O, 18 O, 32 P, 33 P, 33 S, 34 S, 35 S, 36 S, 18 F, 36 C1, 82 Br, 123 1, 124 1, 129 I and 131 L
  • Certain isotopic variants of a compound of the invention such as in particular those in which one or more radioactive isotopes are incorporated, may be useful, for example for the study of the mechanism of action or distribution of active ingredient in the body; Due to the comparatively easy production and detectability, compounds labeled with 3 H or 14 C isotopes in particular are
  • the compounds according to the invention can act systemically and / or locally.
  • they may be applied in a suitable manner, for example orally, parenterally, pulmonarily, nasally, sublingually, lingually, buccally, rectally, dermally, transdermally, conjunctivally, otically or as an implant or stent.
  • the compounds according to the invention can be administered in suitable administration forms.
  • suitable for oral administration are all application forms known per se to the person skilled in the art, which can rapidly deliver the compounds according to the invention.
  • the compounds according to the invention may in this case be present in crystalline, amorphous or dissolved form, for example in tablets (non-coated or coated tablets, for example with enteric or delayed-dissolving or insoluble coatings which control the release of the compound according to the invention), in the oral cavity rapidly disintegrating tablets , in films / wafers, in films / lyophilisates, in capsules (for example hard or soft gelatin capsules), in dragees, in granules, in pellets, in powders, in emulsions, in suspensions, in aerosols or in solutions.
  • the parenteral administration can be done bypassing a resorption step
  • intravenously, intraarterially, intracardially, intraspinal or intralumbar or with the involvement of a resorption (for example, intramuscularly, subcutaneously, intracutaneously, percutaneously or intraperitoneally).
  • parenteral administration are suitable as application forms u.a.
  • Injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.
  • inhalant medicaments including powder inhalers, Vernebier
  • nasal drops solutions, sprays
  • lingual, sublingual or buccal tablets to be applied, films / wafers or capsules, suppositories, ear or
  • Ophthalmic preparations vaginal capsules, aqueous suspensions (lotions, shake mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (such as patches), milk, pastes, foams, scattering powders, implants or stents.
  • excipients include, but are not limited to, excipients (eg, microcrystalline cellulose, lactose, mannitol), solvents (For example, liquid polyethylene glycols), emulsifiers and dispersing or wetting agents (for example, sodium dodecyl sulfate, Polyoxysorbitanoleat), binders (for example, polyvinylpyrrolidone), synthetic and natural polymers (for example, albumin),
  • excipients eg, microcrystalline cellulose, lactose, mannitol
  • solvents for example, liquid polyethylene glycols
  • emulsifiers and dispersing or wetting agents for example, sodium dodecyl sulfate, Polyoxysorbitanoleat
  • binders for example, polyvinylpyrrolidone
  • synthetic and natural polymers for example, albumin
  • Stabilizers for example, antioxidants such as ascorbic acid
  • dyes for example, inorganic pigments such as iron oxides
  • flavor and / or odoriferous for example, antioxidants such as ascorbic acid
  • Stabilizers for example, antioxidants such as ascorbic acid
  • dyes for example, inorganic pigments such as iron oxides
  • Another object of the present invention are pharmaceutical compositions containing the compounds of the invention, usually together with one or more inert, non-toxic, pharmaceutically suitable excipients and their use for the purposes mentioned above.
  • the formulation of the compounds according to the invention into pharmaceutical preparations is carried out in a manner known per se to the person skilled in the art by converting the active substance (s) into the desired administration form with the auxiliaries customary in galenicals.
  • excipients for example, vehicles, fillers, disintegrants,
  • Binders humectants, lubricants, ab- and adsorbents, diluents, solvents, cosolvents, emulsifiers, solubilizers, flavoring agents,
  • the pharmaceutical formulations may be in solid form, for example as tablets, dragees, pills, suppositories, capsules, transdermal systems or in semi-solid form, for example as ointments, creams, gels, suppositories, emulsions or in liquid form, for example as solutions, Tinctures, suspensions or emulsions are present.
  • auxiliaries may be, for example, salts, saccharides (mono-, di-, tri-, oligo- and / or polysaccharides), proteins, amino acids, peptides, fats, waxes, oils,
  • Hydrocarbons and derivatives thereof, wherein the excipients may be of natural origin or may be obtained synthetically or partially synthetically.
  • the compounds according to the invention are suitable for the prophylaxis and / or therapy of hyperproliferative diseases such as, for example, psoriasis, keloids and other skin-related hyperplasias, and for the prophylaxis and / or therapy of benign prostate hyperplasia (BPH), solid tumors and hematological tumors.
  • hyperproliferative diseases such as, for example, psoriasis, keloids and other skin-related hyperplasias
  • BPH benign prostate hyperplasia
  • tumors of the breast, the respiratory tract, the brain, the reproductive organs, the gastrointestinal tract, the genitourinary tract, the eye, the liver, the skin, the head and neck, the thyroid gland, the parathyroid gland are treatable Bone and connective tissue and metastases of these tumors.
  • a hematological tumor multiple myelomas, lymphomas or leukemias are treatable.
  • Breast tumors are treatable breast cancers with positive breast cancers
  • non-small cell cancers are treatable as tumors of the respiratory tract
  • tumors of the brain are treatable by gliomas, glioblastomas, astrocytomas, meningiomas and medulloblastomas.
  • tumors of the male reproductive organs are treatable
  • Prostate carcinomas malignant epididymal tumors, malignant testicular tumors and penile carcinomas.
  • tumors of the female reproductive organs are treatable.
  • Endometrial carcinoma cervical carcinoma, ovarian carcinoma, vaginal carcinoma and
  • Vulvarkarzinome For example, treatable tumors of the gastrointestinal tract are colorectal carcinomas, anal carcinomas, gastric carcinomas, pancreatic carcinomas, esophageal carcinomas.
  • Gallbladder carcinomas small bowel carcinomas, salivary gland carcinomas, neuroendocrine tumors and gastrointestinal stromal tumors.
  • tumors of the urogenital tract are treatable by bladder carcinomas, renal cell carcinomas, and carcinomas of the renal pelvis and the urinary tract.
  • tumors of the eye are treatable retinoblastomas and intraocular Melanoma.
  • Treatable hepatocellular carcinomas and cholangiocellular carcinomas are tumors of the liver.
  • treatable tumors of the skin are malignant melanomas, basaliomas,
  • tumors of the head and neck are treatable with laryngeal carcinomas and carcinomas of the pharynx and oral cavity.
  • soft-tissue sarcomas and osteosarcomas are treatable as sarcomas.
  • non-Hodgkin's lymphomas For example, non-Hodgkin's lymphomas, Hodgkin's lymphomas, cutaneous lymphomas, central nervous system lymphomas, and AIDS-associated lymphomas are treatable as lymphomas.
  • Treatable as leukemias are acute myeloid leukemias, chronic myeloid leukemias, acute lymphatic leukemias, chronic lymphocytic leukemias and hair cell leukemias.
  • the compounds according to the invention can be used for the prophylaxis and / or therapy of leukemias, in particular acute myeloid leukemias,
  • Prostate cancer especially androgen receptor-positive prostate cancer
  • Hormone receptor-positive or BRCA-associated breast carcinoma pancreatic carcinoma, renal cell carcinoma, hepatocellular carcinoma, melanoma and other skin tumors, non-small cell lung carcinoma, endometrial carcinoma and colorectal carcinoma.
  • the compounds according to the invention can be used particularly advantageously for the prophylaxis and / or therapy of leukemias, in particular acute myeloid leukemias, prostate carcinomas, in particular androgen receptor-positive prostate carcinomas,
  • Breast cancer in particular estrogen receptor-alpha negative breast carcinoma, melanoma or multiple myeloma.
  • the compounds according to the invention are also suitable for the prophylaxis and / or therapy of benign hyperproliferative diseases such as, for example, endometriosis, leiomyoma and benign prostatic hyperplasia.
  • benign hyperproliferative diseases such as, for example, endometriosis, leiomyoma and benign prostatic hyperplasia.
  • systemic inflammatory diseases in particular LPS-induced endotoxic shock and / or bacteria-induced sepsis.
  • the compounds according to the invention are also suitable for the prophylaxis and / or therapy of inflammatory or autoimmune diseases such as, for example:
  • Pulmonary diseases with inflammatory, allergic and / or proliferative disorders Pulmonary diseases with inflammatory, allergic and / or proliferative disorders
  • Associated processes chronic obstructive pulmonary disease of any genesis, especially bronchial asthma; Bronchitis of different origin; all forms of restrictive lung diseases, especially allergic alveolitis; all forms of pulmonary edema, especially toxic pulmonary edema; Sarcoidoses and granulomatoses, in particular Boeck's disease, - Rheumatic diseases / autoimmune diseases / joint diseases associated with inflammatory, allergic and / or proliferative processes: all forms of rheumatic diseases, in particular rheumatoid arthritis, acute rheumatic fever, polymyalgia rheumatica; reactive arthritis; Inflammatory soft tissue diseases of other origin; arthritic symptoms in degenerative joint disease
  • Insect bites Insect bites, allergic reactions to drugs, blood derivatives, contrast agents, etc., anaphylactic shock, urticaria, contact dermatitis,
  • Vasculitides Panarteritis nodosa, temporal arteritis, erythema nodosum,
  • atopic dermatitis Psoriasis; Pityriasis rubra pilaris; erythematous diseases induced by different noxae, e.g. Blasting, chemicals, burns etc .; bullous dermatoses; Diseases of the lichenoid type; pruritus; seborrheic eczema; rosacea; Pemphigus vulgaris; Erythema exudative multiforme; balanitis; vulvitis; Hair loss such as alopecia areata; cutaneous T-cell lymphoma,
  • Kidney diseases associated with inflammatory, allergic and / or proliferative processes nephrotic syndrome; all nephritis, Liver diseases associated with inflammatory, allergic and / or proliferative processes: acute liver cell decay; acute hepatitis of various causes, such as viral, toxic, drug-induced; chronic aggressive and / or chronic intermittent hepatitis,
  • Gastrointestinal disorders associated with inflammatory, allergic and / or proliferative processes regional enteritis (Crohn's disease); Ulcerative colitis; Gastritis; reflux esophagitis; Gastroenteritides of other genesis, for example, gluten-sensitive enteropathy (native sprue),
  • Proctological diseases associated with inflammatory, allergic and / or proliferative processes analgesic; fissures; Hemorrhoids; idiopathic proctitis,
  • Neurological diseases associated with inflammatory, allergic and / or proliferative processes brain edema, especially tumor-related cerebral edema; multiple sclerosis; acute encephalomyelitis; Meningitis; various forms of seizures, such as BNS cramps,
  • Blood disorders associated with inflammatory, allergic and / or proliferative processes acquired hemolytic anemia; idiopathic thrombocytopenia,
  • Tumor diseases associated with inflammatory, allergic and / or proliferative processes acute lymphoblastic leukemia; malignant lymphomas; Lymphogranulomatosen; lymphosarcoma; extensive metastases, especially in breast, bronchial and prostate cancers,
  • Endocrine disorders associated with inflammatory, allergic and / or proliferative processes endocrine orbitopathy; thyrotoxic crisis; Thyreoditis de Quervain; Hashimoto's thyroiditis; Graves' disease,
  • Severe states of shock such as anaphylactic shock, systemic inflammatory response syndrome (SIRS),
  • hypopituitarism acquired secondary adrenal insufficiency, for example, postinfectious, tumors, etc.
  • Emesis associated with inflammatory, allergic and / or proliferative processes for example in combination with a 5-HT3 antagonist in cytostatic vomiting,
  • Pain of inflammatory genesis e.g. Lumbago.
  • the compounds according to the invention are also suitable for the treatment of viral
  • the compounds of the invention are also useful in the treatment of atherosclerosis, dyslipidemia, hypercholesterolemia, hypertriglyceridemia, peripheral vascular disorders, cardiovascular disorders, angina, pectoris, ischemia, stroke, myocardial infarction, angioplasty restenosis, hypertension, thrombosis, obesity, endotoxemia.
  • the compounds according to the invention are also suitable for the treatment of
  • neurodegenerative diseases such as multiple sclerosis, Alzheimer's disease and Parkinson's disease.
  • Another object of the present invention relates to the use of
  • Another object of the present invention relates to the use of
  • Androgen receptor-positive prostate carcinomas cervical carcinomas, breast cancers, especially of hormone receptor-negative, hormone receptor-positive or BRCA-associated Breast carcinoma, pancreatic carcinoma, renal cell carcinoma, hepatocellular carcinoma, melanoma and other skin tumors, non-small cell lung carcinoma,
  • Endometrial carcinomas and colorectal carcinomas are endometrial carcinomas and colorectal carcinomas.
  • Another object of the present invention relates to the use of
  • Estrogen receptor-alpha negative breast carcinoma melanoma or multiple myeloma.
  • Another object of the invention is the use of the compounds of the invention for the manufacture of a medicament.
  • Another object of the present invention relates to the use of
  • Another object of the present application relates to the use of
  • breast cancer in particular hormone receptor-negative, hormone receptor-positive or BRCA-associated breast carcinoma, pancreatic carcinoma, renal cell carcinoma,
  • Hepatocellular carcinomas melanomas and other skin tumors, non-small cell lung carcinomas, endometrial carcinomas and colorectal carcinomas.
  • Another object of the present invention relates to the use of
  • leukemias in particular acute myeloid leukemias, prostate carcinomas, in particular androgen receptor-positive prostate carcinomas, breast carcinomas, in particular estrogen receptor-alpha negative breast carcinomas, melanomas or multiple myelomas.
  • Another object of the present invention relates to the use of
  • Another object of the present invention relates to the use of
  • Androgen receptor-positive prostate carcinomas cervical carcinomas, breast cancers, especially of hormone receptor-negative, hormone receptor-positive or BRCA-associated Breast carcinomas, pancreatic carcinomas, renal cell carcinomas, hepatocellular carcinomas, melanomas and other skin tumors, non-small cell lung carcinomas,
  • Endometrial carcinoma and colorectal carcinoma are endometrial carcinoma and colorectal carcinoma.
  • Another object of the present invention relates to the use of
  • Estrogen receptor-alpha negative breast carcinoma melanoma or multiple myeloma.
  • a further subject of the present invention relates to pharmaceutical formulations in the form of tablets containing one of the compounds according to the invention for the prophylaxis and / or therapy of leukemias, in particular acute myeloid leukemias,
  • Prostate cancer especially androgen receptor-positive prostate cancer
  • Hormone receptor-positive or BRCA-associated breast carcinomas pancreatic carcinomas, renal cell carcinomas, hepatocellular carcinomas, melanomas and other skin tumors, non-small cell lung carcinomas, endometrial carcinomas and colorectal
  • a further subject of the present invention relates to pharmaceutical formulations in the form of tablets containing one of the compounds according to the invention for the prophylaxis and / or therapy of leukemias, in particular acute myeloid leukemias,
  • Prostate cancer especially androgen receptor-positive prostate cancer
  • Breast cancer in particular estrogen receptor-alpha negative breast carcinoma, melanoma or multiple myeloma.
  • Another object of the invention relates to the use of the invention
  • Another object of the invention relates to the use of the invention
  • the compounds according to the invention can be used alone or as needed in combination with one or more further pharmacologically active substances, as long as this combination does not lead to undesired and unacceptable side effects.
  • Another object of the present invention are therefore pharmaceutical compositions containing a novel Compound and one or more other active ingredients, in particular for the prophylaxis and / or therapy of the aforementioned diseases.
  • the compounds of the invention may be combined with known anti-hyperproliferative, cytostatic or cytotoxic chemical and biological substances for the treatment of cancers.
  • the combination of the compounds according to the invention with other substances commonly used for cancer therapy or also with radiotherapy is particularly indicated.
  • Eflornithine Eligard, Elitek, Ellence, Emend, Enzalutamide, Epirubicin, Epoetin-alfa, Epogen, Epothilone and its Derivatives, Eptaplatin, Ergamisol, Erlotinib, Erythro-Hydroxynonyladenine, Estrace, Estradiol, Estramustine Sodium Phosphate, Ethinylestradiol, Ethyol, Etidronic Acid,
  • Etopophos etoposide, everolimus, exatecan, exemestane, fadrozole, farston, fenretinide, filgrastim, finasteride, fligrastim, floxuridine, fluconazole, fludarabine, 5-fluorodeoxyuridine monophosphate, 5-fluorouracil (5-FU), flu-ioxy-imesterone, flutamide , Folotin, Formestan, Fosteabin, Fotemustin, Fulvestrant, Gammagard, Gefitinib, Gemcitabine, Gemtuzumab, Gleevec, Gliadel, Goserelin, Gossypol, Granisetron hydrochloride, Hexamethylmelamine, Histamine dihydrochloride, Histrelin, Holmium-166-DOTPM, Hycamtin, Hydrocorton, erythro Hydroxynonyladenine, hydroxyurea, hydroxyprogesterone caproate, ibandr
  • Tiludronic acid tipifarnib, tirapazamine, TLK-286, toceranib, topotecan, toremifene,
  • the compounds of the invention can be reacted with antibodies such as e.g.
  • Aflibercept alemtuzumab, bevacizumab, brentuximumab, catumaxomab, cetuximab,
  • the compounds of the invention can be used in combination with anti-angiogenic therapies such as bevacizumab, axitinib, regorafenib, cediranib, sorafenib, sunitinib, lenalidomide, copanlisib or thalidomide.
  • anti-angiogenic therapies such as bevacizumab, axitinib, regorafenib, cediranib, sorafenib, sunitinib, lenalidomide, copanlisib or thalidomide.
  • anti-angiogenic therapies such as bevacizumab, axitinib, regorafenib, cediranib, sorafenib, sunitinib, lenalidomide, copanlisib or thalidomide.
  • antihormones and steroidal metabolic enzyme inhibitors are particularly suitable because of their favorable side effect profile.
  • Combinations with P-TEFb and CDK9 inhibitors are also particularly suitable because of the possible synergistic effects.
  • the following objectives can be pursued with the combination of the compounds according to the invention with other cytostatic or cytotoxic agents:
  • the compounds of the invention may also be used in conjunction with radiotherapy and / or surgical intervention.
  • NMR signals are given with their respective recognizable multiplicity or their combinations.
  • s singlet
  • d doublet
  • t triplet
  • q quartet
  • qi quintet
  • sp septet
  • m multiplet
  • b broad signal.
  • the chemical shifts ⁇ are given in ppm (parts per million).
  • (+) - BINAP R) - (+) - 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl (CAS 76189-55-4)
  • T3P 2,4,6-tripropyl-1, 3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide
  • TBTU benzotriazole-1-ylxy
  • Substitution reactions or other reactions known to the person skilled in the art include reactions that introduce a functional group that allows further conversion of substituents.
  • Suitable protecting groups as well as methods for their introduction and removal are known to those skilled in the art (see, for example, T.W. Greene and P.G.M. Wuts in: Protective Groups in Organic Synthesis, 3rd Edition, Wiley 1999).
  • the combination of two or more reaction steps without intermediate workup in a manner known in the art is possible (for example, in so-called “one-pot” reactions).
  • Enantiomerengemische for example racemates, or occur as pure enantiomers.
  • the enantiomer mixtures mentioned can be prepared by those familiar to the person skilled in the art
  • Pyridine derivatives such as 3-amino-2,6-dichloropyridine ((II), CAS No. 62476-56-6).
  • nitrogen atom-protected amino acids of the formula (III) in which R 4 and R 5 are defined as in the general formula (I), and in which PG is a protective group such as Boc, Cbz or Fmoc with suitable aminopyridine Derivatives, for example, 3-amino-2,6-dichloropyridine ((II), CAS No. 62476-56-6).
  • Coupling reagents such as T3P, TBTU, HATU or DCC used.
  • the conversion of carboxylic acids to their amides is generally described in reference books such as "Compendium of Organic Synthetic Method”, Volume I-VI (Wiley Interscience) or” The Practice of Peptide Synthesis “, Bodansky (Springer Verlag).
  • Compounds of the formula (III) are known to the person skilled in the art and are commercially available.
  • the compounds of the formula (IV) obtained are then converted by deprotection of the protective group PG on the amine by suitable methods to give the compounds of the formula (V).
  • Reductant such as sodium triacetoxyborohydride to the secondary amine of formula (VI) transformed.
  • the secondary amines of the formula (VI) can be converted by cyclization to give dihydropyridopyrazinones of the formula (VII).
  • a suitable base for example a trialkylamine, such as triethylamine or diisopropylethylamine, under elevated temperature (see also WO2010 / 96426 A2, Example 16).
  • Scheme 1 Synthesis of intermediates of formula (VIII) from 3-amino-2,6-dichloropyridine (II).
  • the preparation of intermediates of the formula (VIIa) in which R 6 is unsubstituted or substituted phenyl as defined for R 6 in the general formula (I) is described in Scheme 2.
  • 3-Amino-2,6-dichloropyridine ((II), CAS No. 62476-56-6) is reacted with compounds of the formula (IX) in which R 4 and R 5 are defined as for the general formula (I ), and in which LG and LG 'are each independently a leaving group, preferably chlorine or bromine, such as 2-bromopropionyl bromide (CAS 563-76-8).
  • a geeineten solvent such as dichloromethane or THF
  • a base such as triethylamine, -Diisopropylethylamin or pyridine implemented.
  • the base can also be used as a solvent.
  • the said compounds of the formula (I) are obtained as racemates, provided that R 4 and R 5 are different from one another. If appropriate, these can be separated into the enantiomers using the separation methods familiar to the person skilled in the art, for example preparative HPLC on a chiral stationary phase.
  • the chlorinated intermediates of the formula (VIII) can be obtained by reaction with an aminating reagent, for example 1,1-diphenylmethanimine (XIII), in the presence of a catalytically active palladium reagent, for example
  • an aminating reagent for example 1,1-diphenylmethanimine (XIII)
  • XIII 1,1-diphenylmethanimine
  • R 7 4-fluoronitrobenzene (CAS 350-46-9) or 2-fluoro-5-nitroanisole (CAS 454-16-0) with thiols of the formula R 7 -SH in which R 7 is defined as in the general formula (I)
  • thiols of the formula R 7 -SH in which R 7 is defined as in the general formula (I)
  • methanethiol, ethanethiol, propanethiol, propan-2-thiol, cyclopropanethiol or the other homologous thiols with the addition of a base such as sodium, cesium or potassium carbonate, triethylamine or sodium hydride (eg analogously U. Luecking et al., US2011 / 251222; Kondoh, et al., Tetrahedron (2006), vol 62, p2357-60).
  • Thiols of the formula R 7 -SH are known to the person skilled in the art and are commercially available or are described in great structural
  • compounds according to (XVII) are obtained in which X, Y, R 2 , R 7 and n are defined as in the general formula (I).
  • Compounds of the general formula (XVIII) in which X, Y, R 2 , R 7 and n are defined as in the general formula (I) can be obtained by oxidation of the sulfur atom of the compounds of the formula (XVII) with suitable reagents such as Potassium peroxosulphate (Oxone®, CAS 70693-62-8), meto-chloroperbenzoic acid or
  • Compounds of the general formula (XII) in which A is -N (C 1 -C 3 -alkyl) - corresponding to general formula (I) can be prepared by reaction of compounds of the formula (XIIa) generally known to the person skilled in the art with corresponding aldehydes, such as formaldehyde , Acetaldehyde or propionate dehyd and a reducing agent such as Sodium triacetoxyborohydride or sodium cyanoborohydride, or also by reduction with hydrogen and a corresponding catalyst, e.g. Palladium be obtained on activated carbon.
  • aldehydes such as formaldehyde , Acetaldehyde or propionate dehyd
  • a reducing agent such as Sodium triacetoxyborohydride or sodium cyanoborohydride

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Abstract

L'invention concerne des 3,4-dihydropyrido[2,3-b]pyrazinones inhibitrices de protéine BET, en particulier inhibitrices de BRD4, à groupe éther ou amino aromatique para-substitué, ayant la formule générale (I) dans laquelle A, X, Y, R1, R2, R3, R4, R5, R6 et n ont les significations figurant dans la description, des agents pharmaceutiques contenant les composés selon l'invention, et leur utilisation prophylactique et thérapeutique dans le cadre de maladies hyper-prolifératives, notamment de maladies tumorales. L'invention concerne également l'utilisation d'inhibiteurs de protéine BET dans le cadre d'infections virales, de maladies neurodégénératives, de maladies inflammatoires, de troubles athérosclérotiques et pour le contrôle de la fertilité masculine.
PCT/EP2015/063276 2014-06-18 2015-06-15 Dérivés de dihydropyrido[2,3-b]pyrazinone inhibant la protéine bet, à groupe éther ou amino aromatique para-substitué Ceased WO2015193217A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102017005091A1 (de) 2016-05-30 2017-11-30 Bayer Pharma Aktiengesellschaft Substituierte 3,4-Dihydropyrido[2,3-b]pyrazin-2(1H)-one
DE102017005089A1 (de) 2016-05-30 2017-11-30 Bayer Pharma Aktiengesellschaft Substitulerte 3,4-Dihydrochinoxalin-2(1H)-one

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013027168A1 (fr) * 2011-08-22 2013-02-28 Pfizer Inc. Nouveaux composés hétérocycliques utilisés en tant qu'inhibiteurs de bromodomaine
WO2014095774A1 (fr) * 2012-12-20 2014-06-26 Bayer Pharma Aktiengesellschaft Dihydropyridopyrazinones inhibitrices de protéine bet

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013027168A1 (fr) * 2011-08-22 2013-02-28 Pfizer Inc. Nouveaux composés hétérocycliques utilisés en tant qu'inhibiteurs de bromodomaine
WO2014095774A1 (fr) * 2012-12-20 2014-06-26 Bayer Pharma Aktiengesellschaft Dihydropyridopyrazinones inhibitrices de protéine bet

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102017005091A1 (de) 2016-05-30 2017-11-30 Bayer Pharma Aktiengesellschaft Substituierte 3,4-Dihydropyrido[2,3-b]pyrazin-2(1H)-one
DE102017005089A1 (de) 2016-05-30 2017-11-30 Bayer Pharma Aktiengesellschaft Substitulerte 3,4-Dihydrochinoxalin-2(1H)-one

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